Advisory Committee Chair
Matthew Might
Advisory Committee Members
Farah Lubin
Erik D Roberson
Yuhua Song
David Standaert
Summer B Thyme
Document Type
Dissertation
Date of Award
2023
Degree Name by School
Doctor of Philosophy (PhD) School of Engineering
Abstract
Alzheimer’s disease (AD) is a devastating, complex form of dementia. Contributions from genetics make up almost 70% of a person’s risk of developing AD, but the mechanisms by which this occurs are not well understood. Attempts to tease apart the risk contributions from individual genes have identified lipid processing and activation of innate immunity as convergent pathways for many of the known genetic risk factors. One of the strongest known risk factors, TREM2, codes for a transmembrane receptor that activates a protective immune response when it detects bound lipids. Variants in TREM2 that control AD risk have been identified, but other variants in TREM2 seem to instead increase risk of various other neurodegenerative diseases. This raises questions about what each variant is doing to TREM2’s structure that leads to these different clinical outcomes and whether these different effects can be targeted with potential therapeutics. Here we present a collection of work using computational tools to examine the structural biology of TREM2, with intent both to characterize the structural effects of these variants and to identify potential ligands that may correct these effects. We discover that an apical region of TREM2 with features suitable for lipid binding is disrupted by these variants, with the variants associated with earlier onset diseases causing different magnitudes of disruption. We then identify a potential signaling mechanism, through formation of TREM2 multimers, that may be affected downstream of this disruption. Finally, we use virtual screening to identify vitamin D3 as a novel iv ligand that can bind TREM2, even in the presence of AD-associated variants, and activate its protective cellular responses. Together this work provides a foundation for future studies examining the signaling mechanisms of TREM2 that are downstream of ligand binding and provides a set of testable hypotheses for how different forms of TREM2 may be signaling in disease.
Recommended Citation
Dean, Hunter Byron, "The Effects of Alzheimer's Disease-Associated Variants and Ligands on the Structure And Function of TREM2" (2023). All ETDs from UAB. 441.
https://digitalcommons.library.uab.edu/etd-collection/441